Palliative treatment of uncontrollable hypercalcemia due to parathyrotoxicosis: denosumab as rescue therapy

Parathyroid carcinoma is a rare disease leading to severe hypercalcemia due to hyperparathyroidism. Surgery is the primary treatment option. A more progressive form of the disease is characterized by parathyrotoxicosis, and subsequent hypercalcemia is the most common cause of death. We report a case presenting with severe hypercalcemia due to parathyrotoxicosis from parathyroid carcinoma treated for the first time using the monoclonal antibody denosumab as a rescue therapy and present long-term follow-up data. The 71-year-old patient presented with severe hypercalcemia due to metastatic parathyroid carcinoma. Despite undergoing treatment with bisphosphonates, cinacalcet hydrochloride, and forced diuresis, the patient's condition deteriorated rapidly due to resistant hypercalcemia. Surgery performed because of spinal metastasis and forced diuresis lowered calcium levels, albeit they remained in the hypercalcemic range and significantly increased when forced diuresis was stopped. Considering a palliative situation to overcome hypercalcemia, we decided to administer denosumab, a monoclonal antibody that binds to the receptor activator of nuclear factor-kappa B ligand. After a single subcutaneous administration of 60 mg denosumab, calcium levels normalized within one day. Subsequent denosumab injections led to permanent control of serum calcium for more than 2 years despite rising parathyroid hormone levels and repeated surgeries. Together with recent cases in the literature supporting our observation, we believe that denosumab is relevant for future trials and represents an effective tool to control hypercalcemia in patients with advanced stages of parathyroid cancer

Atrial natriuretic peptide and leptin interactions in healthy men

Introduction: Atrial natriuretic peptide (ANP), a hormone secreted from the heart, controls cardiovascular and renal functions including arterial blood pressure and natriuresis. ANP also exerts metabolic effects in adipose tissue, liver and skeletal muscle, and interacts with the secretion of adipokines. We tested the hypothesis that ANP lowers concentrations of the anorexigenic adipokine leptin in healthy humans in vivo. Methods: Human ANP or matching placebo was infused intravenously (iv) into healthy men in a controlled clinical trial. Results: Within 135 minutes of iv ANP infusion, we observed an acute decrease in plasma leptin levels compared to controls. Free fatty acids markedly increased with ANP infusion in vivo, indicating activated lipolysis. In human SGBS adipocytes, ANP suppressed leptin release. Discussion: The study shows that the cardiac hormone ANP reduces the levels of the anorexigenic adipokine leptin in healthy humans, providing further support for ANP as a cardiomyokine in a heart - adipose tissue axis. (registered in the German Clinical Trials Register and the WHO International Clinical Trials Registry Platform was granted under DRKS00024559)

Atrial natriuretic peptide and leptin interactions in healthy men

INTRODUCTION: Atrial natriuretic peptide (ANP), a hormone secreted from the heart, controls cardiovascular and renal functions including arterial blood pressure and natriuresis. ANP also exerts metabolic effects in adipose tissue, liver and skeletal muscle, and interacts with the secretion of adipokines. We tested the hypothesis that ANP lowers concentrations of the anorexigenic adipokine leptin in healthy humans in vivo. METHODS: Human ANP or matching placebo was infused intravenously (iv) into healthy men in a controlled clinical trial. RESULTS: Within 135 minutes of iv ANP infusion, we observed an acute decrease in plasma leptin levels compared to controls. Free fatty acids markedly increased with ANP infusion in vivo, indicating activated lipolysis. In human SGBS adipocytes, ANP suppressed leptin release. DISCUSSION: The study shows that the cardiac hormone ANP reduces the levels of the anorexigenic adipokine leptin in healthy humans, providing further support for ANP as a cardiomyokine in a heart - adipose tissue axis. (registered in the German Clinical Trials Register and the WHO International Clinical Trials Registry Platform was granted under DRKS00024559

Peripheral Endocannabinoids Associated with Energy Expenditure in Native Americans of Southwestern Heritage

Context: The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as well as the related acylethanolamide oleoylethanolamide (OEA), have been implicated in energy expenditure (EE) regulation and metabolic diseases. Muscle (fat-free mass) and fat (fat mass) are metabolically active compartments and main determinants of EE. Objective: To assess whether human muscle, adipose, and plasma endocannabinoids correlate with EE. Design: Muscle, adipose, and plasma AEA, 2-AG, and OEA concentrations were measured via liquid chromatography-mass spectrometry. EE was assessed by indirect whole-room calorimetry. Setting: Clinical trial. Participants: Obese/overweight Native Americans of full (n = 35) and at least half (n = 21) Southwestern heritage. Main Outcome Measures: Twenty-four-hour EE, sleeping EE (SLEEP), resting EE (REE), respiratory quotient (RQ), and macronutrient oxidation. Results: In full Natives, muscle AEA concentration correlated with SLEEP (r = -0.65, P = 0.004) and REE (r = -0.53, P = 0.02). Muscle 2-AG was associated with SLEEP (r = -0.75, P = 0.0003). Adipose OEA concentration correlated with RQ (r = -0.47, P = 0.04) and lipid oxidation (r = 0.51, P = 0.03). Plasma OEA concentration was associated with SLEEP (r = -0.52, P = 0.04). After adjustment for major determinants, these lipids explained nearly 20% of the additional variance of the respective measure. Similarly, in Native Americans of at least half Southwestern heritage, investigated lipids correlated with EE measures. Conclusion: Endocannabinoids in metabolically relevant peripheral tissues explained a large part of EE variation and may be involved in regulating EE. Dysregulation of peripheral endocannabinoids may predispose people to metabolic diseases via an effect on EE and lipid oxidation

Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide dichlorodiphenyltrichloroethane, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking.This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 years). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose ratios as well as time-in-range (TR) in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane TR was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options

Specific skeletal muscle sphingolipid compounds in energy expenditure regulation and weight gain in Native Americans of Southwestern heritage.

Background/objectivesIn animal models, a role in the regulation of energy expenditure (EE) has been ascribed to sphingolipids, active components of cell membranes participating in cellular signaling. In humans, it is unknown whether sphingolipids have a role in the modulation of EE and, consequently, influence weight gain. The present study investigated the putative association of EE and weight gain with sphingolipid levels in the human skeletal muscle, a component of fat-free mass (the strongest determinant of EE), in adipose tissue and plasma.Subjects/methodsTwenty-four-hour EE, sleeping metabolic rate (SMR) and resting metabolic rate (RMR) were assessed in 35 healthy Native Americans of Southwestern heritage (24 male; 30.2±7.73 years). Sphingolipid (ceramide, C; sphingomyelin, SM) concentrations were measured in skeletal muscle tissue, subcutaneous adipose tissue and plasma samples. After 6.68 years (0.26-12.4 years), follow-up weights were determined in 16 participants (4 females).ResultsConcentrations of C24:0, SM18:1/26:1 and SM18:0/24:1 in muscle were associated with 24-h EE (r=-0.47, P=0.01), SMR (r=-0.59, P=0.0008) and RMR (r=-0.44, P=0.01), respectively. Certain muscle sphingomyelins also predicted weight gain (for example, SM18:1/23:1, r=0.74, P=0.004). For specific muscle sphingomyelins that correlated with weight gain and EE (SM18:1/23:0, SM18:1/23:1 and SMR, r=-0.51, r=-0.41, respectively, all P<0.03; SM18:1/24:2 and RMR, r=-0.36, P=0.03), associations could be reproduced with SMR in adipose tissue (all r<-0.46, all P<0.04), though not in plasma.ConclusionsThis study provides preliminary, novel evidence, that specific muscle and adipose tissue sphingolipid compounds are associated with EE and weight gain in Native Americans of Southwestern heritage. Further studies are warranted to investigate whether sphingolipids of different body compartments act in concert to modulate energy balance in humans

Specific skeletal muscle sphingolipid compounds in energy expenditure regulation and weight gain in Native Americans of Southwestern heritage.

Background/objectivesIn animal models, a role in the regulation of energy expenditure (EE) has been ascribed to sphingolipids, active components of cell membranes participating in cellular signaling. In humans, it is unknown whether sphingolipids have a role in the modulation of EE and, consequently, influence weight gain. The present study investigated the putative association of EE and weight gain with sphingolipid levels in the human skeletal muscle, a component of fat-free mass (the strongest determinant of EE), in adipose tissue and plasma.Subjects/methodsTwenty-four-hour EE, sleeping metabolic rate (SMR) and resting metabolic rate (RMR) were assessed in 35 healthy Native Americans of Southwestern heritage (24 male; 30.2±7.73 years). Sphingolipid (ceramide, C; sphingomyelin, SM) concentrations were measured in skeletal muscle tissue, subcutaneous adipose tissue and plasma samples. After 6.68 years (0.26-12.4 years), follow-up weights were determined in 16 participants (4 females).ResultsConcentrations of C24:0, SM18:1/26:1 and SM18:0/24:1 in muscle were associated with 24-h EE (r=-0.47, P=0.01), SMR (r=-0.59, P=0.0008) and RMR (r=-0.44, P=0.01), respectively. Certain muscle sphingomyelins also predicted weight gain (for example, SM18:1/23:1, r=0.74, P=0.004). For specific muscle sphingomyelins that correlated with weight gain and EE (SM18:1/23:0, SM18:1/23:1 and SMR, r=-0.51, r=-0.41, respectively, all P<0.03; SM18:1/24:2 and RMR, r=-0.36, P=0.03), associations could be reproduced with SMR in adipose tissue (all r<-0.46, all P<0.04), though not in plasma.ConclusionsThis study provides preliminary, novel evidence, that specific muscle and adipose tissue sphingolipid compounds are associated with EE and weight gain in Native Americans of Southwestern heritage. Further studies are warranted to investigate whether sphingolipids of different body compartments act in concert to modulate energy balance in humans

Thrifty energy phenotype predicts weight regain - results of a randomized controlled trial

BACKGROUND & AIMS: Weight loss is associated with an improvement of insulin sensitivity. Both, a negative energy balance and changes of body composition are integrative components of weight loss interventions. However, the individual impact of these two components on insulin sensitivity and energy metabolism is unclear. METHODS: We performed a randomized controlled trial including 80 overweight or obese post-menopausal women. Participants randomly assigned to the intervention group underwent an 800 kcal/d liquid diet for 2 months followed by four weeks in which the formula diet was substituted by a calorie reduced healthy diet to facilitate further weight loss. This weight loss phase was followed by a 4-week weight maintenance phase, where weight stability was achieved by individualized daily caloric intake without negative energy balance. Volunteers of the control group were instructed to keep their weight stable during the entire period of 4 months. Metabolic phenotyping was performed in both groups at baseline (M0), after weight loss (M3) and after the maintenance period (M4). Additional phenotyping was performed during follow-up at 12 (M12) and 24 months (M24). Primary outcomes were changes of lean body mass (LBM) and changes of insulin sensitivity (ISI(Clamp)) between baseline and M3 and M4. Estimates of energy metabolism were secondary endpoints. RESULTS: No significant changes of body weight or LBM were found in the control group between any time points. A significant reduction of body weight, fat mass (FM) and LBM was found in the intervention group between M0 and M3, while no further change was seen between M3 and M4. Only subjects of the intervention group were characterized by an improvement of the second primary outcome ISI(Clamp) at M3, which was preserved until M4. Notably, a lower resting energy expenditure per LBM (REE(LBM)) at M3 as well as the individual difference of REE(LBM) between M3 and M4 significantly predicted a stronger regain of fat mass during follow-up. CONCLUSIONS: In summary, our data demonstrate that modulation of LBM and insulin sensitivity during weight loss is predominantly driven by changes in body weight and body composition, rather than an individual effect of negative energy balance. However, the variance in energy expenditure during negative and steady energy balance indicates a thrifty phenotype, which is highly susceptible to future regain of fat mass

Weight loss partially restores glucose-driven betatrophin response in humans

Context: Recently a potential role of betatrophin was shown in the postprandial switch from lipid to glucose metabolism. Objective: To analyse whether obesity is associated with altered postprandial betatrophin response and whether this could be restored by weight loss. Design, Setting, Participants, Intervention: Oral glucose load was performed in 12 lean individuals at baseline as well as in 20 obese subjects before and after a 12-week structured weight loss program at an endocrinology research center. Euglycemic hyperinsulinemic clamps were performed in the obese cohort. Effect of insulin and different glucose concentrations on betatrophin expression were analysed in 3T3-L1 adipocytes. Main Outcome Measure: Circulating betatrophin levels during glucose challenge. Results: Betatrophin level decreases after an oral glucose intake (p<0.001). This correlates with the increase of glucose levels (r=-0.396; p<0.05). Hyperinsulinemia results in an increase of betatrophin. In vitro experiments in 3T3-L1 adipocytes confirmed that insulin and low glucose concentration increases betatrophin expression, whereas further elevation of glucose levels blunts this effect. Obese subjects are characterized by lower fasting betatrophin (600.6±364.4 vs. 759.5±197.9 pg/ml; p<0.05) and a more pronounced betatrophin suppression during the glucose challenge. The impaired betatrophin response in obese subjects is restored after weight loss and comparable to lean individuals. Conclusions: Obesity is associated with increased betatrophin suppression after an oral glucose load, which is driven by increased hyperglycemia. Given the metabolic properties of betatrophin, this may indicate that betatrophin is tightly linked to obesity-associated metabolic disturbances. In line with such an assumption weight loss almost completely eliminated this phenomenon. Obesity is associated with altered postprandial betatrophin response, which seems to be driven by increased hyperglycemia. Weight loss almost completely eliminates this phenomenon